C. difficile associated diarrhea (CDAD) is the leading cause of nosocomial diarrhea. Treatment with metronidazole or vancomycin further suppresses normal flora and contributes to the 15-25% relapse rate and prolonged shedding of the organism. CDAD epidemics and community acquisition suggest that the nature of CDAD is changing. Toxinotype III, NAP1/027/BI strains (BI), although present since 1984, now have quinolone resistance, and they have been associated with increased disease severity. Additionally, a naturally occurring strain, 8864, toxin A-/B+, with variant toxin B, has been shown to cause increased mortality and diarrhea in mouse and hamster models, respectively. There is not a consensus as to the nature of the relationship of these characteristics, risk factors for acquisition, or detailed clinical course of patients with these emerging strains versus traditional strains. Building upon experience in a pioneering enteric pathogenesis laboratory, expertise in public health sciences, the UVA data repository, and collaborations with TechLab, this project will launch critical studies with the emerging strains to evaluate risk factors and impact, in preparation for innovative approaches to prevention and control. This study engages the investigator with university/industry collaborations that specifically advance her career goals of conducting clinical trials. The specific aims are to (1) conduct a retrospective case-control analysis to identify risk factors for adults developing non-epidemic CDAD caused by BI;(2) perform a prospective case-control analysis to evaluate the clinical course of adult patients with non-epidemic BI CDAD;and (3) determine the effects of clinically isolated BI strains on disease and mortality in the Syrian hamster model and the effects of purified toxins associated with BI on secretion and histological changes in the rabbit ileal loop model. The project will also examine the effects of strain 8864 in these 2 animal models in preparation for testing novel approaches to disease control. The answers to these questions will offer an improved understanding of the emerging CDAD, so as to lead to improved treatment strategies for this worrisome evolving disease using newly developing approaches, whether by binding toxin(s) (Louie, Peppe et al. 2006) or by pharmacologically blocking or reversing their effects, as done by our group (Cavalcante, Castro et al. 2006).